Streptococcus pneumoniae is the leading etiological agent of severe infections such as pneumonia, meningitis and sepsis. Young children, elderly and immunocompromised individuals are particularly vulnerable for pneumococcal diseases, which result in high morbidity and mortality (Hausdorff, W. P. et al., 2005, Lancet Infect. Dis. 5:83-93). The currently available vaccines against pneumococcal infections are based on serotype-specific capsular polysaccharides. These include a vaccine containing solely polysaccharides of 23 serotypes and a conjugate vaccine consisting of polysaccharides of the 7 most prevalent paediatric serotypes conjugated to an immunogenic carrier protein. The latter vaccine was introduced for the use in children under the age of 5, since their immune response to pure polysaccharides is inadequate. The introduction of this conjugate vaccine in the national vaccination program in the United States has had a major effect on invasive pneumococcal disease incidence (Whitney, C. G. et al., 2003, N. Eng. J. Med. 348:1737-1746).
Since at least 90 different polysaccharide structures are currently known within the species, polysaccharide-based vaccines only protect against a limited number of serotypes and hence, replacement by non-vaccine serotypes remains a threat for vaccine efficacy (Bogaert, D. et al., 2005, J. Clin. Microbiol. 43:74-83). Further, high production costs of the conjugate vaccines make their use in developing countries less feasible.
Treatment of Streptococcus pneumoniae infections is also impeded by the rise of strains resistant to the most commonly applied antibiotics (Levy, S. B. and Marshall, B., 2004, Nat. Med. 10:S122-S129). The development of an affordable effective vaccine against invasive pneumococcal disease in, especially, young children and elderly will have major benefits in terms of reducing disease burden and health care costs in both developed and developing countries. Immunogenic antigens of pneumococcal origin that are conserved amongst numerous serotypes would be desirable for conferring protection against infections caused by a broad range of serotypes. Much research effort is currently invested in search for pneumococcal proteins with protective potential to be included in future vaccines.
Methods searching for surface proteins of Streptococcus pneumoniae have been described (e.g. WO 98/18930), other methods have used immunological approaches to find possible antigenic determinants (WO 01/12219). On a genetic level, several methods have been used to determine which genes are needed by Streptococcus pneumoniae in the various niches it occupies in the host (conditionally essential genes) such as transcriptome analysis (Orihuela, C. J. et al., 2004, Infect. Immun. 72:4766-4777), differential fluorescence induction (Marra, A. et al., 2002, Infect. Immun. 70:1422-1433) and signature-tagged mutagenesis (Hava, D. L. and Camilli, A., 2002, Mol. Microbiol. 45:1389-1406; Lau, G. W. et al., 2001, Mol. Microbiol. 40:555-571; Polissi, A. et al., 1998, Infect. Immun. 66:5620-5629). Through these and other methods, several pneumococcal proteins have been identified and further investigated as potential vaccine candidates, such as the toxoid derivative of pneumolysin (PdB) (Briles, D. E. et al., 2003, J. Infect. Dis. 188:339-348; Ogunniyi, A. D. et al., 2000, Infect. Immun. 68:3028-3033; Ogunniyi, A. D. et al., 2001, Infect. Immun. 69:5997-6003), pneumococcal surface protein A (PspA) (Briles, D. E. et al., 2003, supra; Briles, D. E. et al., 2000, Infect. Immun. 68:796-800; Swiatlo, E. et al., 2003, Infect. Immun. 2003, 71:7149-7153; Wu, H. Y. et al., 1997, J. Infect. Dis. 175:839-846), pneumococcal surface adhesion A (PsaA) (Briles, D. E. et al., 2000, supra), choline binding protein A (CbpA) (Ogunniyi, A. D. et al., 2000, supra), BVH-3 (Hamel, J. et al., 2004, Infect. Immun. 72:2659-2670), PiuA and PiaA (Brown, J. S. et al., 2001, Infect. Immun. 69:6702-6706), pneumococcal protective protein A (PppA) (Green, B. A. et al., 2005, Infect. Immun. 73:981-989), putative proteinase maturation protein A (PpmA) (Adrian, P. V. et al., 2004, Vaccine 22:2737-2742; Overweg, K. et al., 2000, Infect. Immun. 68:4180-4188), IgA1 protease (IgAlp) (Weiser, J. N. et al., 2003, Proc. Natl. Acad. Sci. USA 100:4215-4220) and the streptococcal lipoprotein rotamase A (SlrA) (Adrian, P. V. et al. supra).
Yet, there is still need for new vaccine candidates.